Mitofusin 2 deficiency causes pro-inflammatory effects in human primary macrophages

  • Mitofusin 2 (MFN2) is a mitochondrial outer membrane GTPase, which modulates mitochondrial fusion and affects the interaction between endoplasmic reticulum and mitochondria. Here, we explored how MFN2 influences mitochondrial functions and inflammatory responses towards zymosan in primary human macrophages. A knockdown of MFN2 by small interfering RNA decreased mitochondrial respiration without attenuating mitochondrial membrane potential and reduced interactions between endoplasmic reticulum and mitochondria. A MFN2 deficiency potentiated zymosan-elicited inflammatory responses of human primary macrophages, such as expression and secretion of pro-inflammatory cytokines interleukin-1β, -6, -8 and tumor necrosis factor α, as well as induction of cyclooxygenase 2 and prostaglandin E2 synthesis. MFN2 silencing also increased zymosan-induced nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinases inflammatory signal transduction, without affecting mitochondrial reactive oxygen species production. Mechanistic studies revealed that MFN2 deficiency enhanced the toll-like receptor 2-dependent branch of zymosan-triggered responses upstream of inhibitor of κB kinase. This was associated with elevated, cytosolic expression of interleukin-1 receptor-associated kinase 4 in MFN2-deficient cells. Our data suggest pro-inflammatory effects of MFN2 deficiency in human macrophages.
Author:Vera Khodzhaeva, Yannick Schreiber, Gerd GeisslingerORCiDGND, Ralf BrandesORCiDGND, Bernhard BrüneORCiD, Dmitry Namgaladze
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Document Type:Article
Date of Publication (online):2021/08/12
Date of first Publication:2021/08/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/08/30
Tag:endoplasmic reticulum; inflammation; macrophages; mitochondria; mitochondrial dynamics; zymosan
Issue:art. 723683
Page Number:15
First Page:1
Last Page:15
This study was supported by the grants from Deutsche Forschungsgemeinschaft (SFB 1039, Teilprojekt A01, A05, B04, and Z01).
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0